Clinical Efficacy

Life’s little victories start with profound seizure reduction

The safety and effectiveness of FINTEPLA for the treatment of seizures associated with Dravet syndrome were established in 2 randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in patients 2 to 18 years of age.

Results from Study 1 evaluating the safety and efficacy of FINTEPLA in patients with Dravet syndrome

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Study 1 (N=117) compared 0.7 and 0.2 mg/kg/day FINTEPLA with placebo in patients who were inadequately controlled on 1-4 concomitant antiepileptic drugs and had a minimum of 6 convulsive seizures during the baseline period. The primary efficacy endpoint was the change from baseline in the frequency of convulsive seizures per 28 days during the combined 14-week titration and maintenance periods (ie, treatment period). The median longest interval between convulsive seizures was also assessed.

Reduction in convulsive seizure frequency from baseline

FINTEPLA 0.7 mg/kg/day reduced monthly convulsive seizures a median of 79.4% from baseline over 14 weeks.1

  • The placebo-adjusted percent reduction in monthly convulsive seizure frequency was 70.0% for FINTEPLA 0.7 mg/kg/day (P<.001) and 31.7% for FINTEPLA 0.2 mg/kg/day (P=.043)
  • A reduction in convulsive seizures was observed within 3 to 4 weeks of starting FINTEPLA, and the effect remained generally consistent over the 14-week treatment period

Reduction in Convulsive Seizure Frequency From Baseline (Study 1)1

Proportion of patients with ≥50% or ≥75% reduction in convulsive seizure frequency

The majority of patients (70%) taking FINTEPLA 0.7 mg/kg/day over 14 weeks experienced a 50% or greater reduction in monthly convulsive seizures.

  • 7 in 10 patients had a clinically meaningful (≥50%) reduction
  • More than 1 in 2 patients had a profound (≥75%) reduction

Proportion of Patients Achieving ≥50% or ≥75% Reduction in Convulsive Seizures From Baseline (Study 1)

Median longest seizure-free interval

50% of patients taking FINTEPLA 0.7 mg/kg/day over 14 weeks achieved a seizure-free (0 seizures) interval lasting at least 21 days vs 8 days in the placebo group.

Patients in Study 1 had an average of 1.5 seizures per day at baseline.1

Median Longest Seizure-Free Interval (Study 1)

Seizure freedom is possible

8% of patients taking FINTEPLA 0.7 mg/kg/day reported no convulsive seizures during the entire 14 weeks vs 0 patients in the placebo group.

Proportion of Patients Who Had 0 Seizures Over 14 Weeks (Study 1)

Results of a post hoc analysis of patients who had 0 or 1 seizure over 14 weeks

1 in 4 patients taking FINTEPLA 0.7 mg/kg/day had no more than a single seizure during the 14-week treatment period.1

  • Because these results were obtained in a post hoc analysis, no conclusions of efficacy should be made

At baseline, patients in Study 1 experienced a mean of 41 seizures per month.1

Proportion of Patients Who Had 0 or 1 Seizure Over 14 Weeks (Study 1)1

FINTEPLA demonstrated significant efficacy when added to stiripentol

Results from Study 2 evaluating the safety and efficacy of FINTEPLA in patients with Dravet syndrome receiving stiripentol and either clobazam, valproate, or both

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Study 2 (N=85) compared 0.4 mg/kg/day FINTEPLA with placebo in patients who were inadequately controlled on 2-4 concomitant antiepileptic drugs (including stiripentol and either clobazam, valproate, or both) and had a minimum of 6 convulsive seizures during the baseline period. The primary efficacy endpoint was the change from baseline in the frequency of convulsive seizures per 28 days during the combined 15-week titration and maintenance periods (ie, treatment period). The median longest interval between convulsive seizures was also assessed. The 0.4 mg/kg/day dose was not an intermediate dose. Patients on the 0.4 mg/kg/day dose were also taking concomitant stiripentol (with clobazam and/or valproate), which increases exposure of FINTEPLA.

Reduction in convulsive seizure frequency from baseline

FINTEPLA 0.4 mg/kg/day reduced monthly convulsive seizures 63.1% from baseline.1

  • The placebo-adjusted percent reduction in monthly convulsive seizure frequency was 59.5% (P<.001)

Reduction in Convulsive Seizure Frequency From Baseline (Study 2)1

All patients in both study groups were receiving stiripentol and either clobazam, valproate, or both.

Proportion of patients with a profound (≥75%) reduction in convulsive seizure frequency

The majority of patients (53.5%) taking FINTEPLA 0.4 mg/kg/day over 15 weeks experienced a 50% or greater reduction in monthly convulsive seizures.

  • More than 1 in 3 patients experienced a 75% or greater reduction in convulsive seizures

Proportion of Patients Achieving ≥50% or ≥75% Reduction in Convulsive Seizures From Baseline (Study 2)

aP value vs placebo.

All patients in both study groups were receiving stiripentol and either clobazam, valproate, or both.

Long-term extension study

Results from a long-term (3-year), open-label extension study of FINTEPLA in patients with Dravet syndrome

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Open-label extension study results
  • 94% of patients who completed Study 1 or Study 2 participated in a long-term, flexible-dose, open-label extension study
  • All patients were started at a dose of 0.2 mg/kg/day and were subsequently titrated up to their maintenance dose
  • The results of this open-label, uncontrolled study are exploratory; therefore, no conclusions of efficacy should be made

In controlled and uncontrolled trials, 341 patients were treated with FINTEPLA, including 312 treated for >6 months, 284 for >1 year, and 138 for >2 years.

Reduction in Convulsive Seizure Frequency Over Time1

The number of patients assessed at each time point is shown in the figure. The decrease in patient number is primarily due to staggered entry into the study.

FINTEPLA study designs

The safety and effectiveness of FINTEPLA for the treatment of seizures associated with Dravet syndrome were established in 2 randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in patients 2 to 18 years of age.

Patient selection

Patients had a clinical diagnosis of Dravet syndrome and seizures that were inadequately controlled on at least 1 antiepileptic drug (AED) or treatment including vagal nerve stimulation or ketogenic diet.

Seizure types

Convulsive seizure types assessed included tonic, clonic, generalized tonic-clonic, tonic-atonic, secondarily generalized tonic-clonic, hemiclonic, and focal with observable motor signs.

Study 1 description
Study 1
(N=117)
Study groups 0.7 mg/kg/daya
0.2 mg/kg/daya
Placebo
Baseline convulsive seizure frequency ≥6 over 6 weeks, with a mean of 41 (median of 22) per month1
Concomitant AEDs Stiripentol was not allowed in this study
98% of patients were taking 1-4 concomitant AEDs, including
valproate (61%), clobazam (59%), and topiramate (25%)
Primary endpoint Change from baseline in frequency of monthly convulsive seizures with FINTEPLA vs placebo

aStudy 1 compared 2 doses of fenfluramine, 0.7 mg/kg/day and 0.2 mg/kg/day, with placebo in patients who were not receiving stiripentol.

Study 2 description
Study 2
(N=85)
Study groups 0.4 mg/kg/dayb
Placebo
Baseline convulsive seizure frequency ≥6 over 6 weeks, with a mean of 26
(median of 12) per month1
Concomitant AEDs All patients were also on stiripentol
100% of patients were taking 2-4 concomitant AEDs, including stiripentol (100%), clobazam (94%), and valproate (89%)
Primary endpoint Change from baseline in frequency of monthly convulsive seizures with FINTEPLA vs placebo

bStudy 2 compared 1 dose of fenfluramine, 0.4 mg/kg/day, with placebo in patients who were receiving stiripentol and either clobazam, valproate, or both. The 0.4 mg/kg/day dose accounted for a drug interaction between stiripentol and fenfluramine and was designed to approximate the 0.7 mg/kg/day dose evaluated in Study 1.

FINTEPLA Study 1 and Study 2 timelines

Long-term extension study
  • 94% of patients who completed Study 1 or Study 2 participated in a long-term, flexible-dose, open-label extension study
  • The study evaluated the safety and antiseizure activity of FINTEPLA
References
  • Data on file, Zogenix, Inc.
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INDICATIONS AND USAGE

FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: VALVULAR HEART DISEASE and PULMONARY ARTERIAL HYPERTENSION

  • There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension.
  • Echocardiogram assessments are required before, during, and after treatment with FINTEPLA.
  • FINTEPLA is available only through a restricted program called the FINTEPLA REMS.

CONTRAINDICATIONS

FINTEPLA is contraindicated in patients with hypersensitivity to fenfluramine or any of the excipients in FINTEPLA and with concomitant use of, or within 14 days of, the administration of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome.

WARNINGS AND PRECAUTIONS

Valvular Heart Disease and Pulmonary Arterial Hypertension (see Boxed Warning): Because of the association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension, cardiac monitoring via echocardiogram is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can aid in early detection of this condition. In clinical trials of up to 3 years in duration, no patient receiving FINTEPLA developed valvular heart disease or pulmonary arterial hypertension.

Monitoring: Prior to starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease and pulmonary arterial hypertension. Echocardiograms should be repeated every 6 months, and once at 3-6 months post treatment with FINTEPLA.

If valvular heart disease or pulmonary arterial hypertension is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA.

FINTEPLA REMS Program (see Boxed Warning): FINTEPLA is available only through a restricted distribution program called the FINTEPLA Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified by enrolling in the FINTEPLA REMS. Prescribers must counsel patients receiving FINTEPLA about the risk of valvular heart disease and pulmonary arterial hypertension, how to recognize signs and symptoms of valvular heart disease and pulmonary arterial hypertension, the need for baseline (pretreatment) and periodic cardiac monitoring via echocardiogram during FINTEPLA treatment, and cardiac monitoring after FINTEPLA treatment. Patients must enroll in the FINTEPLA REMS and comply with ongoing monitoring requirements. The pharmacy must be certified by enrolling in the FINTEPLA REMS and must only dispense to patients who are authorized to receive FINTEPLA. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

Decreased Appetite and Decreased Weight: FINTEPLA can cause decreases in appetite and weight. Decreases in weight appear to be dose related. Most patients resumed the expected measured increases in weight by the end of the open-label extension study. Weight should be monitored regularly during treatment with FINTEPLA and dose modifications should be considered if a decrease in weight is observed.

Somnolence, Sedation, and Lethargy: FINTEPLA can cause somnolence, sedation, and lethargy. Other central nervous system (CNS) depressants, including alcohol, could potentiate these effects of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA to gauge whether it adversely affects their ability to drive or operate machinery.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behaviors in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviors, or any unusual changes in mood or behavior.

Anyone considering prescribing FINTEPLA or any other AED must balance the risk of suicidal thoughts or behaviors with the risks of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviors. Should suicidal thoughts and behaviors emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Withdrawal of Antiepileptic Drugs: As with most AEDs, FINTEPLA should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Serotonin Syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with FINTEPLA, particularly during concomitant administration of FINTEPLA with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements (eg, St. John’s Wort, tryptophan), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs], which are contraindicated with FINTEPLA), dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity. Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If serotonin syndrome is suspected, treatment with FINTEPLA should be stopped immediately and symptomatic treatment should be started.

Increase in Blood Pressure: FINTEPLA can cause an increase in blood pressure. Significant elevation in blood pressure, including hypertensive crisis, has been reported rarely in adult patients treated with fenfluramine, including patients without a history of hypertension. Monitor blood pressure in patients treated with FINTEPLA. In clinical trials of up to 3 years in duration, no patient receiving FINTEPLA developed hypertensive crisis.

Glaucoma: Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Consider discontinuing treatment with FINTEPLA in patients with acute decreases in visual acuity or ocular pain.

ADVERSE REACTIONS

The most common adverse reactions (incidence at least 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus.

DRUG INTERACTIONS

Strong CYP1A2 and CYP2B6 Inducers: Coadministration with rifampin or a strong CYP1A2 and CYP2B6 inducer will decrease fenfluramine plasma concentrations. Consider an increase in FINTEPLA dosage when coadministered with rifampin or a strong CYP1A2 and CYP2B6 inducer.

USE IN SPECIFIC POPULATIONS

Administration to patients with moderate or severe renal impairment or to patients with hepatic impairment is not recommended.

Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.